As hormone replacement therapy, various kinds of sex hormones have heretofore been administered in the forms of oral preparations, injection preparations, transdermal preparations, and the like, as in the cases of the administration of androgen, such as testosterone, for the purpose of improving male hypogonadism, and the administration of a female sex hormone, such as estrogen (estradiol, or the like) or progestogen (progesterone, or the like) for the purpose of improving menopausal disorders and osteoporosis of females or preventing conception. Also, dehydroepiandrosterone, which is a precursor of androgen and estrogen, has heretofore been used clinically as a treatment medicine for adrenalism and systemic lupus erythematosus.
In the sex hormone replacement therapy, a natural type sex hormone, which is biosynthetically produced in a living organism, and a synthetic sex hormone, which is synthesized artificially, are used. In cases where the natural type sex hormone is administered orally, absorption from the digestive canal is scarce, and metabolism in the liver is markedly quick. Therefore, it is necessary for the natural type sex hormone to be administered at a high dose and a plurality of times. Particularly, in the cases of the oral administration of progesterone, which is the natural type progestogen, since bioavailability is markedly low, intramuscular injections, and the like, which impose a heavy burden on patients, are employed as principal administration routes. Recently, various kinds of synthetic type sex hormones, whose pharmacological activity, stability, and the like, have been enhanced over the natural type sex hormone, have been developed, and oral preparations containing the synthetic type sex hormones have been marketed. However, uneasiness has increased about side effects of the administration of the synthetic sex hormones, such as the increase of the risk of breast cancer, and the like, due to the long-term use of the synthetic sex hormones in the hormone replacement therapy. From the view point of risks and benefits, the method using the natural type sex hormone so as to replace the natural type sex hormone that is present in the living organism and that has become insufficient, which method is the original form of the sex hormone replacement therapy, has again attracted particular attention.
Since the bioavailability of the natural type sex hormone by the oral administration is markedly low as described above, in order for the first-pass effect in the liver to be avoided, a transdermally absorbable preparation containing progesterone, estradiol, or the like, has been developed (reference may be made to, for example, non-patent literature 1). However, a satisfactory formulation which brings about sufficiently high and long-acting transdermal absorption such that a systemic effect aiming at the hormone replacement therapy is obtained has not yet been obtained. For example, since progesterone is metabolized even in a skin by 5α-reductase present in the skin, in order for progesterone in a quantity effective for treatment to be delivered from the skin for the purpose of the systemic effect, a markedly high skin permeation rate and the keeping thereof are necessary.
In order for the transdermal absorption of an active drug to be enhanced, there have been made various attempts, such as devising of a form of the administered preparation and the use of a skin permeation enhancer. For example, in patent literatures 1 and 2, transdermal patches containing progesterone or estrogen are described. Also, in patent literatures 3 and 4, transdermal formulations containing estrogen or progesterone, in which specific skin permeation enhancement agents are contained, are described. Further, in patent literature 5, a gel formulation, in which a specific hydrophilic copolymer, a polyhydric alcohol, and an active drug, such as progesterone or estradiol, are contained, is described.
However, the patches have the problems in that, since the drugs must ordinarily be contained with comparatively high concentrations in the preparations for obtaining the systemic effect, and the hormone replacement therapy ordinarily requires the treatment over a long period of time, eruptions of the skins, and the like, occur, and in that, since it is necessary for removal of body hairs to be performed with respect to certain patients, compliance decreases.
Also, as for the preparations in which the skin permeation enhancers are contained, there is the risk of the problems occurring with regard to the side effect, such as skin irritation, and the safety. Further, since the majority of the permeation enhancers increase the solubility of the natural type sex hormones acting as the active ingredients, but decrease thermodynamical activity of the active ingredients on the skins after being applied, expectedly large permeation enhancement effects have not yet been obtained.
Ordinarily, in order for the permeation rate of the drug to be increased in the process of the skin permeation of the drug from a transdermal formulation, it is necessary that the thermodynamical activity of the drug on the skin after being applied is increased, and that the drug solubility in the skin barrier primarily constituted of the stratum corneum is increased. Also, from the view point of the preparation stability and appearance, it is necessary that a sufficient drug solubility in the preparation is obtained. With the conventional techniques, particularly with respect to the hydrophobic drug, such as progesterone, a large quantity of a solvent is required for obtaining the sufficient solubility in the preparation. However, the acquisition of the drug solubility in the preparation by the containing of the large quantity of the solvent decreases the thermodynamical activity of the drug on the skin after being applied and, consequently, could not bring about the sufficient and long-acting skin permeation of the drug.
Patent Literature 1:
Japanese Patent No. 3086288
Patent Literature 2:
PCT International Patent Publication No. WO 96/15776
Patent Literature 3:
Japanese Unexamined Patent Publication No. 10 (1998)-72351
Patent Literature 4:
PCT Japanese Publication No. 2001-505930
Patent Literature 5:
Japanese Unexamined Patent Publication No. 9 (1997)-176049
Non-Patent Literature 1:
Menopause, Vol. 12, No. 2, pp. 232-237, 2005